Adsorption of solutions onto the materials of containers that are used to store and transport drugs has been well documented. For example, reductions in the potency of digitoxin, insulin, mithramycin and vincristine sulfate have been noted upon passage of these drugs through in-line intravenous filters containing man-made materials, such as cellulose ester membranes.
Protein is adsorbed by most such man-made materials, including liquid containers made of various polymers, such as cellulose esters. For example, protein adsorption is a concern for wearers of plastic contact lenses. Protein from the tears of contact lens wearers can be adsorbed onto the contact lens surface. The protein can dry and, in the process, distort the smooth surface of that lens, clouding the vision of the wearer.
Polymeric liquid containers, tubing and filters are used to contain, transport and filter protein-containing solutions, such as blood, and solutions containing the proteins like albumin, porcine insulin, human chronic gonadotrophin (HCG), bovine serum albumin, and sheep immunoglobulin G (IgG). Some of these proteins are adsorbed into the artificial polymeric surface, resulting in a lowering of the protein content in that solution. In some applications, this protein adsorption is not a concern, as the protein content is not critical. To compensate for protein adsorption in such instances, an excess of protein is placed in many of these protein-containing solutions. In this way, protein can be adsorbed out of these prior protein-containing solutions without compromising the quality or efficacy of those solutions.
In instances where the quantity of protein administered to a patient is important and where that protein is administered by solution to that patient, the amount of protein administered can be determined indirectly by a process called patient "titration." For example, the actual amount of insulin received by a diabetic patient can be determined by measuring the blood glucose level of that patient after administration of the theoretically correct insulin dosage. If the blood glucose level after administration is still unacceptably high, then the medical professional would infer that a part of the theoretically correct insulin dosage has been lost, prior to ingestion by the patient, to polymeric storage, transport or filtration units. To compensate for this loss, an additional amount of insulin necessary to attain the desired blood glucose level can then be determined and administered. This method of compensation for inaccurately administered drug dosages has been accepted because a biological endpoint is readily determined and the drug is relatively inexpensive.
Some prior art solutions, however, including blood or protein drug solutions, can be adversely affected by protein adsorption onto artificial surfaces. For example, protein adsorption from blood may induce thrombus, i.e., vessel-clogging blood clot, in the patient receiving the blood. Denaturation, a process described below, may occur in a protein drug solution.
In addition, certain newly-created genetically engineered "bio-tech" drugs are especially sensitive. Novel plant- or animal-based bio-tech drugs on the market or being developed include colony stimulating factors, growth factors and hormones, interferons, interleukins, and monoclonal antibodies. Because of the biological specificity of these agents, they are effective even when administered in amounts much smaller than those of many more conventional drugs. It is this smaller dose size that renders these drugs more susceptible to adsorptive protein losses. The amount of protein in these bio-tech drugs is measured in parts per million (ppm), rather than in weight or volume percentages. Conventional containers are unsuitable for these new bio-tech drugs, as even minuscule protein adsorption onto those containers can reduce their level of protein to a point where those drugs are unusable. Moreover, even if the protein is not permanently adsorbed onto the polymeric container, protein molecules can be adsorbed onto the container and then released. This adsorption and release can change the shape of the molecule, a process known as denaturation. When protein molecules in a bio-tech drug or protein drug solution have undergone denaturation, there is a significant risk that they will lose their efficacy and utility.
Because bio-tech drugs can cost several thousand dollars per dose, it is imperative that neither the small amount of protein nor the nature of the protein in those solutions be changed. Moreover, the regulatory agency approvals of this class of susceptible drugs increase rapidly with each passing year.
One method of inhibiting protein loss from protein-containing solutions is the addition of poly(ethylene oxide)-containing surfactants to protein solutions. The addition of poly(ethylene oxide) stabilizes these aqueous proteins. It would be preferable, however, to store protein solutions in containers which do not adsorb proteins, rather than add surfactants to the solutions. The addition of any surfactant in the protein solution will result in the administration of the surfactant to the patient, allowing for the possibility of an adverse reaction.
In attempts to achieve this objective, a protein-compatible material containing the water-soluble polymer poly(ethylene oxide) (PEO) has been manufactured by the present inventors. In the present context, the term "protein-compatible" shall mean a material which (a) absorbs lower amounts of protein than conventional polymeric materials when placed in contact with protein-containing solutions; and (b) lowers the potential for denaturation, as compared to conventional materials currently being used to contain protein-containing solutions. These efforts were directed to PEO because of its apparent high effectiveness as a protein-compatible material. This protein compatibility is believed to be attributable to stearic stabilization effects of PEO, its unique solution properties, and its molecular conformation in aqueous solution.
Prior to the present invention, however, PEO and other water-soluble polymers could not be used in direct contact with protein-water solutions, as such polymers were deemed soluble in aqueous solutions. Thus, research efforts have been directed to methods of providing water-soluble polymer-type protein compatibility in polymers which will contact protein-containing water solutions. The major objective in these efforts was to prevent the solubility of the water-soluble polymer coating of the matrix polymer back into the aqueous protein solution.
PEO has been chemically bonded through graft copolymerization onto polyvinylchloride, styrene-butadiene-styrene, and many other substrates. Surface grafting and solvent swelling are relatively complex manufacturing processes requiring multiple treatment steps. One of the most difficult of these steps is the removal of the solvent or residual reactive ingredients. Such methods or other modification procedures are expensive, however, and thus not the most cost effective method of immobilizing PEO molecules on polymeric surfaces.
Relevant United States patents include U.S. Pat. Nos. 3,222,314, 3,425,981, 3,426,107, 3,524,905, 3,549,727, 3,645,939, 3,789,085, 4,048,131, 4,228,250, 4,327,009, 4,337,188, 4,362,844, 4,412,025, 4,415,691, 4,464,438, 4,500,677, 4,522,967, 4,600,404, 4,600,746, 4,681,526, 4,701,360, 4,768,376, 4,789,575, 4,802,943, 4,859,513, 4,880,701, 4,883,699, 4,888,222, 4,920,158, 4,948,640, 4,981,739, 4,983,431, 4,988,546, 5,045,594, 5,013,769, 5,023,036 and RE 33,376.